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    • 专利摘要:
    Ketogenic compositions enriched with the beta-hydroxybutyrate S (BHB) enantiomer, including a non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate, are formulated to control body levels of ketone in a subject. The non-racemic mixture of BHB is enriched with the S enantiomer to modulate the effect of ketone bodies on the subject and control the rate at which ketosis is obtained. In some respects, a composition to control body level of ketone in a subject contains a dietetically or pharmaceutically acceptable carrier and a non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate, where the non-racemic mixture contains about 52% to 99% by enantiomeric equivalents of S beta-hydroxybutyrate enantiomer and from about 48% to about 1% by enantiomeric equivalents of R beta-hydroxybutyrate enantiomer.
    公开号:BR112020012469A2
    申请号:R112020012469-9
    申请日:2018-11-20
    公开日:2020-11-24
    发明作者:Gary Millet
    申请人:Axcess Global Sciences, Llc；
    IPC主号:
    专利说明:

    [001] [001] Non-racemic beta-hydroxybutyrate compounds, salts, esters, and compositions enriched with the beta-hydroxybutyrate S enantiomer and methods for controlling and / or modulating blood levels and / or the effects of ketone bodies on a body are disclosed here subject.
    [002] [002] In periods of fasting, extreme exercise and / or low carbohydrate consumption, the reserves of glucose and glycogen in the body are used up quickly and can be depleted quickly. Failure to replenish glucose stores as they run out causes the body to shift metabolically to the creation and use of ketone bodies as energy ("ketosis"). Ketone bodies can be used by the body's cells as fuel to satisfy the body's energy needs, including the brain and heart. During prolonged fasting, for example, blood ketone levels can increase to 2 to 3 mmol / L or more.
    [003] [003] After the transition to ketosis, or in other words, during ketogenic metabolism in the liver, the body uses dietary and body fats as the primary source of energy. Consequently, once in ketosis, one can induce the loss of body fat, controlling the dietary fat intake and maintaining low carbohydrate intake and blood level to support ketosis.
    [004] [004] While in ketosis, the body is in ketogenesis and essentially burns fat as the primary fuel. The body breaks down fats into fatty acids and glycerol and transforms fatty acids into acetyl-CoA molecules, which are subsequently transformed through ketogenesis into water-soluble ketone bodies beta-hydroxybutyrate (“β-hydroxybutyrate” or “BHB”) , acetoacetate (also known acetylacetonate) and acetone in the liver. Beta-hydroxybutyrate and acetoacetate are the ketone bodies used by the body for energy, while acetone is removed and expelled as a by-product of ketogenesis.
    [005] [005] The metabolism of ketone bodies is associated with several beneficial effects, including anticonvulsant effects, improved brain metabolism, neuroprotection, muscle-sparing properties and enhanced cognitive and physical performance. Science-based improvements in the efficiency of cellular metabolism, managed through ketone supplementation, can have beneficial impacts on physical, cognitive and psychological health and a long-term health impact with respect to common preventable diseases such as obesity, cardiovascular disease, neurodegenerative diseases, diabetes and cancer.
    [006] [006] Despite the many health benefits of following a ketogenic diet or lifestyle and maintaining a state of nutritional ketosis, there are still significant barriers to seeking and maintaining a ketogenic state. One of these barriers is the difficulty of transition to a ketogenic state. The fastest endogenous way to enter ketosis by depleting glucose reserves in the body is fasting combined with exercise. This is physically and emotionally demanding and is extremely challenging, even for the most motivated and disciplined.
    [007] [007] Additionally, the transition to ketosis is often accompanied by hypoglycemia, which can cause lethargy and dizziness in many, resulting in an uncomfortable physiological and mental state, commonly called "low-carb flu". In addition, many people suffer from a negative regulation of metabolism, as the body naturally goes into an “energy saving” mode. Some suggest that these transient symptoms can last up to two to three weeks. During this transition period, if an individual consumes a meal or snack containing carbohydrates above the restrictive amount, there is an immediate end to ketogenesis, leaving the body from its state of ketosis, as the body returns to using glucose as a primary fuel. and the transition to ketosis must start again.
    [008] [008] If a subject is successful in establishing ketosis, the act of sustaining ketosis is equally difficult, if not more difficult, due to the need to maintain a strict proportion of carbohydrates and proteins and fats in the diet. It is further complicated by the disruption of normal electrolyte balances that generally occur when making the transition and maintaining a ketogenic state. The depletion and reduction of glycogen reserves in the liver and muscles decreases the body's ability to retain water, leading to more frequent urination and, consequently, greater loss of electrolytes. In addition, the drop in insulin levels caused by ketosis affects the rate at which certain electrolytes are extracted by the kidneys, further decreasing the levels of electrolytes in the body. The negative effects of electrolyte imbalance include muscle pain, spasms, nervous tics and weaknesses, restlessness, anxiety, frequent headaches, extreme thirst, insomnia, fever, heart palpitations or irregular heartbeat, digestive problems such as cramps, constipation or diarrhea, confusion and concentration of problems, bone disorders, joint pain, changes in blood pressure, changes in appetite or body weight, fatigue (including chronic fatigue syndrome), numbness in the joints and dizziness, especially when you get up suddenly.
    [009] [009] Some compositions used to promote ketosis in a mammal include a racemic mixture of beta-hydroxybutyrate (RS beta-hydroxybutyrate or DL-beta-hydroxybutyrate). Other compositions, such as those disclosed in U.S. Patent Publication No. 2017/0296501 to Lowery et al., Contain only the endogenous form of beta-hydroxybutyrate, or R beta-hydroxybutyrate, and none of the non-endogenous enantiomer, or S beta-hydroxybutyrate. Others, such as those disclosed in U.S. Patent No. 2017/0296501 to Clarke et al., Consist mainly or entirely of a single beta-hydroxybutyrate (3R) -hydroxybutyl (3R) -hydroxybutyrate ester. Other enantiomers, such as (3R) -hydroxybutyl (3S) -hydroxybutyrate, (3S) -hydroxybutyl (3R) - hydroxybutyrate, and (3S) -hydroxybutyl (3S) -hydroxybutyrate, are mostly or entirely omitted. The omission of enantiomers that are not the endogenous form of beta-hydroxybutyrate is based on the view that S beta-hydroxybutyrate (aka (3S) - hydroxybutyrate) is ineffective or even harmful. BRIEF SUMMARY
    [010] [010] Compositions and methods for controlling bodily levels of ketone in a subject, including promoting and / or prolonging ketosis in a subject over an extended period of time, are disclosed here. Example compositions include a non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate, wherein the non-racemic mixture contains 52% to 99% by enantiomeric equivalents of the S beta-hydroxybutyrate enantiomer and 48% to 1% by enantiomeric equivalents. of the R beta-hydroxybutyrate enantiomer.
    [011] [011] The non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate contains more of the S enantiomer of S beta-hydroxybutyrate than the endogenous form (R-enantiomer) produced by a mammal in order to provide a more controlled and ketogenic effect sustained compared to a racemic mixture and / or compositions enriched with the R enantiomer. Because the R beta-hydroxybutyrate enantiomer is endogenously produced by a mammal during ketosis, administering the R beta-hydroxybutyrate enantiomer to a subject provides an amount that it can be used immediately by the body, as to produce energy (for example, as an alternative energy source to glucose). However, this effect is modulated and extended when the S enantiomer is the predominant component.
    [012] [012] Unlike compositions that are deliberately enriched with the R enantiomer or that minimize or eliminate S beta-hydroxybutyrate completely, the non-racemic mixture is enriched with the S beta-hydroxybutyrate enantiomer, which is not endogenously produced by a mammal, in order to produce one or more desired effects on the mammal, as discussed here.
    [013] [013] In some embodiments, the compositions disclosed herein may be used in a method to increase the body's level of ketone in a subject, including promoting and / or prolonging ketosis in a subject, comprising administering to a subject in need thereof a quantity nutritionally or pharmaceutically effective one or more of the compositions disclosed herein. Examples of beneficial effects of increasing body level of ketone in a subject include one or more of appetite suppression, weight loss, fat loss, reduced blood glucose level, improved mental alertness, increased physical energy, improved of cognitive function, reduction in traumatic brain injury, reduction in the effect of diabetes, improvement of neurological disorder, reduction of cancer, reduction of inflammation, anti-aging, anti-glycation, reduction in epilepsy crisis, improvement of mood, increase in resistance, increase in mass muscle, or improved body composition.
    [014] [014] In some modalities, administering the non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate in the enantiomeric ratios or percentages disclosed here provides one or more of: increased endogenous production of R beta-hydroxybutyrate and acetoacetate; endogenous conversion of S beta-hydroxybutyrate into one or both of R beta-hydroxybutyrate and acetoacetate; endogenous conversion of S beta-hydroxybutyrate into fatty acids and sterols; prolonged ketosis; metabolism of S beta-hydroxybutyrate independent of conversion to R beta-hydroxybutyrate and / or acetoacetate; increased fetal development; increase in years of growth; reduced endogenous acetone production during ketosis; signaling by S beta-hydroxybutyrate that modulates metabolism of R beta-hydroxybutyrate and glucose; antioxidant activity; and production of acetyl-CoA.
    [015] [015] In some embodiments, S beta-hydroxybutyrate or non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate is a solid, such as a powder, crystalline or compressed material. In some embodiments, the composition may include a carrier, such as a liquid, gel or solid. In some embodiments, the composition may include a carrier and up to 100% S beta-hydroxybutyrate enantiomer and no R beta-hydroxybutyrate enantiomer.
    [016] [016] Additional features and benefits will be set out in part in the description below and in part will be obvious from the description, or can be learned by practicing the modalities disclosed here. It should be understood that both the brief summary above and the detailed description below are only exemplary and explanatory and are not restrictive of the modalities disclosed in this document or as claimed.
    [017] [017] As used here, “beta-hydroxybutyrate,” also known as β-hydroxybutyrate, βHB or BHB, means a compound having the general formula CH3CH2OHCH2COOH and the following chemical structure:
    [018] [018] Whether beta-hydroxybutyrate is the S or R enantiomer depends on the tetrahedral orientation of the hydroxy (or oxy group in the case of an ester) on carbon 3 (beta-carbon) in relation to the planar carboxyl group.
    [019] [019] Beta-hydroxybutyrate, typically R beta-hydroxybutyrate, which is the endogenous form, can be used by a patient's body as a fuel source during cases of low glucose levels in the subject or when a patient's body is supplemented with a usable form of beta-hydroxybutyrate. Beta-hydroxybutyrate is commonly referred to as a "ketone body".
    [020] [020] As used here, a “ketogenic composition” is formulated to increase the body's ketone level in a subject, including inducing and / or prolonging a state of elevated ketone bodies to a desired level, such as ketosis, in a subject. which is administered.
    [021] [021] As used herein, "subject" or "patient" refers to members of the animal kingdom, including mammals, such as, without limitation, humans and other primates; rodents, fish, reptiles and birds. The subject can be any animal that requires therapy, treatment or prophylaxis, or any animal suspected of requiring therapy, treatment or prophylaxis. Prophylaxis means that the regiment is carried out to prevent a possible occurrence, such as where a high glucose or diabetes is identified.
    [022] [022] "Ketosis" as used herein refers to a subject having blood ketone levels within the range of about 0.5 mmol / L and about 16 mmol / L in a subject.
    [023] [023] In some cases, “elevated body level of ketone” may not mean that a subject is in a state of “clinical ketosis” but nevertheless has a high supply of ketones to produce energy and / or perform other beneficial effects on bodies of ketone. For example, a subject who is "ketone-adapted" may not necessarily have high serum levels of ketone bodies but is able to use available ketone bodies more quickly compared to a subject who is not "ketone-adapted". In such a case, “elevated body level of ketone” may refer to the total amount and / or rate of ketone bodies being used by the subject instead of plasma blood levels per se.
    [024] [024] The term “medium chain triglycerides” (MCT) refers to molecules having a glycerol backbone attached to three medium chain fatty acids. Medium chain fatty acids can range from 6 to 12 carbon atoms in length, and most likely 8 to 10 carbon atoms in length. Exemplary fatty acids are caprylic acid, also known as octanoic acid, comprising 8 carbon molecules, and capric acid, also known as decanoic acid, comprising 10 carbon molecules. MCTs, medium chain fatty acids, and mono- and di-glycerides are bodily precursors of ketone that can provide an additional source for the production of beta-hydroxybutyrate-independent ketone bodies.
    [025] [025] The term "administration" or "administering" is used here to describe the process in which the disclosed compositions are delivered to a subject. The composition can be administered in a variety of ways, including oral, intragastric and parenteral (referring to intravenous and intra-arterial routes and other appropriate parenteral routes), among others.
    [026] [026] Compositions for increasing the body's ketone level in a subject, including controlling and / or modulating ketosis, comprise a non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate, where the non-racemic mixture contains 52% to 99% by enantiomeric equivalents of the S beta-hydroxybutyrate enantiomer and 48% to 1% by enantiomeric equivalents of the R beta-hydroxybutyrate enantiomer.
    [027] [027] In some embodiments, the non-racemic mixture of R beta-hydroxybutyrate and S beta-hydroxybutyrate contains from 53% to 98%, 55% to 96%, 57% to 93%, 60% to 90%, or 65% 85% by enantiomeric equivalents of the S beta-hydroxybutyrate enantiomer and 47% to 2%, 45% to 4%, 3% to 7%, 40% to 10%, or 35% to 15%, by enantiomeric equivalents of the enantiomer of R beta-hydroxybutyrate.
    [028] [028] The non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate contains more of the S beta-hydroxybutyrate enantiomer instead of the endogenous form produced by a mammal, which is the R beta-hydroxybutyrate enantiomer, in order to provide a more controlled, gradual, extended, and / or modulated ketogenic effect compared to a racemic mixture or composition enriched with the R beta-hydroxybutyrate enantiomer. Because the R beta-hydroxybutyrate enantiomer is endogenously produced by a mammal during ketosis, administering the R beta-hydroxybutyrate enantiomer to a subject provides an additional amount and / or increased blood plasma level that can be used immediately by the body, as for produce energy (for example, as an alternative energy source for glucose). However, this effect is modulated and extended due to the S enantiomer being the predominant component.
    [029] [029] Unlike compositions that deliberately minimize or eliminate S beta-hydroxybutyrate, the non-racemic mixture contains a majority of the S-beta-hydroxybutyrate enantiomer, which is not endogenously produced by a mammal, in order to produce one or more effects desired in the mammal. For example, administering S beta-hydroxybutyrate together with R beta-hydroxybutyrate can result in at least one of: (1) increased endogenous production of R beta-hydroxybutyrate and acetoacetate; (2) endogenous conversion of S beta-hydroxybutyrate into one or both of R beta-hydroxybutyrate and acetoacetate; (3) endogenous conversion of S beta-hydroxybutyrate into fatty acids and sterols; (4) prolonged ketosis; (5) metabolism of S beta-hydroxybutyrate independent of conversion to R beta-hydroxybutyrate and / or acetoacetate; (6) increased fetal development; (7) increased years of growth; (8) reduced endogenous acetone production during ketosis; (9) signaling by S beta-hydroxybutyrate that modulates the metabolism of R beta-hydroxybutyrate and glucose; (10) antioxidant activity; and (11) production of acetyl-CoA.
    [030] [030] The non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate can be used, for example, to produce one or more desired effects on the subject, including but not limited to, appetite suppression, weight loss, weight loss fat, reduced blood glucose levels, improved mental attention, increased physical energy, improved cognitive function, reduced traumatic brain injury, reduced diabetes effect, improved neurological disorder, reduced cancer, reduced inflammation, anti-aging, anti-glycation, reduction in epilepsy crisis, improved mood, increased resistance, increased muscle mass or improved body composition.
    [031] [031] In some embodiments, the composition may include a carrier and up to 100% S beta-hydroxybutyrate enantiomer and no R beta-hydroxybutyrate enantiomer.
    [032] [032] S beta-hydroxybutyrate and R beta-hydroxybutyrate can be supplied in various forms, such as salts and esters. The percentage of equivalent enantiomers of each of S beta-hydroxybutyrate and R beta-hydroxybutyrate is defined by the molar amount of S beta-hydroxybutyrate or R beta-hydroxybutyrate divided by the total molar amount of both S beta-hydroxybutyrate and R beta- hydroxybutyrate.
    [033] [033] In some embodiments, the non-racemic mixture of R beta-hydroxybutyrate and S beta-hydroxybutyrate is provided in a composition that includes a dietetically or pharmaceutically acceptable carrier. Examples include powders, liquids, tablets, capsules, food products, food additives, beverages, beverage additives, candies, suction cups, lozenges, food supplements, sprays, injectables and suppositories.
    [034] [034] In some embodiments, the non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate can be supplied as a salt, as one or more alkali metal salts, alkaline earth metals, transition metals, amino acids or amino acid metabolites . Examples include lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts, zinc salts, iron salts (such as iron II and / or iron III), chromium salts, manganese salts, salts of cobalt, copper salts, molybdenum salts, selenium salts, arginine salts, lysine salts, leucine salts, isoleucine salts, histidine salts, ornithine salts, citrulline salts, glutamine salts and creatine salts.
    [035] [035] In some embodiments, the non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate can be supplied as one or more esters, such as mono-, di-, tri-, oligo- and polyesters. Examples include ethanol monoester, 1-propanol monoester, 1,2-propanediol monoester, 1,2-propanediol diester, 1,3-propanediol monoester, 1,3-propanediol diester, monoester of S-, R-, or SR-1,3-butanediol, S-, R- diester, or SR-1,3-butanediol, glycerin monoester, (3S) -hydroxybutyl (3S) -hydroxybutyrate monoester , (3R) -hydroxybutyl (3S) -
    [036] [036] In some embodiments, the composition may also include at least one medium chain fatty acid, or a mono-, di- or triglyceride of at least one medium chain fatty acid, where the medium chain fatty acid has to 6 to 12 carbons, preferably 8 to 10 carbons. Although less preferred, the composition may comprise at least one short chain fatty acid, or a mono-, di- or triglyceride of at least one short chain fatty acid, having less than 6 carbons and / or at least one fatty acid long-chain, or a mono-, di- or triglyceride of at least one long-chain fatty acid, having more than 12 carbons.
    [037] [037] Examples and sources of medium chain fatty acid, or an ester thereof as a medium chain triglyceride, include coconut oil, coconut milk powder, fractionated coconut oil, palm oil, palm kernel oil, acid caprylic, capric acid, isolated medium chain fatty acids, such as hexanoic acid isolated, isolated octanoic acid, isolated decanoic acid, medium chain triglycerides, purified or in natural form, such as coconut oil, and ester derivatives of ethoxylated fatty acid triglycerides medium chain, enonic triglyceride derivatives, aldehyde derivatives of triglycerides, derivatives of monoglycerides, derivatives of diglycerides and derivatives of triglycerides and salts of medium chain triglycerides.
    [038] [038] Administration of a non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate results in controlled, prolonged, and modulated blood levels of ketone bodies, thereby exploiting the metabolic and physiological benefits of sustained ketosis. Increased levels of ketone bodies in the blood provide the individual with greater flexibility in dietary options compared to methods that aim to induce and sustain ketosis based on diet alone (for example, based on fasting and / or limited intake of carbohydrates). For example, a subject who has been given an appropriate amount of a non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate may be able to occasionally eat carbohydrate or sugar-based foods, without compromising the ketogenic state and returning to the state glucose-based metabolic.
    [039] [039] In some embodiments, a ketogenic composition additionally includes a therapeutically effective amount of vitamin D3. Vitamin D3 is believed to work in conjunction with magnesium and calcium to promote good bone health and to prevent undesirable soft tissue calcification. In preferred embodiments, vitamin D3 is included in an amount so that an average daily dose of the ketogenic composition includes about 200 IU ("International Units") at about 8000 IU, or about 400 IU at about 4000 IU, or about 600 IU to about 3000 IU of vitamin D3. In some embodiments, vitamin D3 is included in an amount so that an average daily dose of the ketogenic composition includes about 5 µg to about 200 µg, or about 10 µg to about 100 µg, or about 15 µg at about 75 µg of vitamin D3.
    [040] [040] Some modalities also include one or more additional ketone precursors or supplements. These additional ketone precursors or supplements may include acetoacetate, ketone esters and / or other compounds that cause an increase in blood ketone levels without adding more electrolytes to the bloodstream. Other additives include metabolites that enhance the effect or transport of ketone bodies to mitochondria, caffeine, theobromine and nootropics, such as L-alpha glycerylphosphorylcholine ("alpha GPC").
    [041] [041] The composition may include flavoring agents that help to mask the bad taste of beta-hydroxybutyrate compounds. This includes essential oils such as peppermint, natural and artificial sweeteners and other flavorings known in the art.
    [042] [042] In some embodiments, ketogenic compositions may also include one or more additional components configured to decrease the hygroscopicity of the composition. For example, various anti-caking agents, flow agents and / or moisture absorbers, in types and quantities safe for consumption, may be included. Such additional components may include one or more of an aluminosilicate, ferrocyanide, carbonate or bicarbonate salt, silicate (for example, sodium or calcium silicate), phosphate salt (for example, tricalcium phosphate), talc, powdered cellulose, and similar.
    [043] [043] In some embodiments, the compositions disclosed herein can be used in a method to increase the body's level of ketone, including promoting and / or prolonging ketosis, in a subject comprising administering to a subject in need thereof a nutritionally or pharmaceutically amount effectiveness of one or more compositions disclosed here. Examples of beneficial effects of increasing the body's ketone level, including promoting and / or prolonging ketosis, in a subject include one or more appetite suppression, weight loss, fat loss, reduced blood glucose level, improved mental attention, increase in physical energy, improvement in cognitive function, reduction in traumatic brain injury, reduction in the effect of diabetes, improvement in neurological disorder, reduction in cancer, reduction in inflammation, anti-aging, anti-glycation, reduction in epilepsy crisis, improvement in mood, increased stamina, increased muscle mass or improved body composition.
    [044] [044] In some modalities, administering the non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate in the enantiomeric ratios or percentages disclosed here provides one or more of increased endogenous production of R beta-hydroxybutyrate and acetoacetate; endogenous conversion of S beta-hydroxybutyrate into one or both of R beta-hydroxybutyrate and acetoacetate; endogenous conversion of S beta-hydroxybutyrate into fatty acids and sterols; prolonged ketosis; metabolism of S beta-hydroxybutyrate independent of conversion to R beta-hydroxybutyrate and / or acetoacetate; increased fetal development; increase in years of growth; reduced endogenous acetone production during ketosis; signaling by S beta-hydroxybutyrate that modulates the metabolism of R beta-hydroxybutyrate and glucose; antioxidant activity; and production of acetyl-CoA.
    [045] [045] The ketogenic compositions described here can be administered to a subject in therapeutically effective dosages and / or at frequencies to induce or sustain ketosis. In some embodiments, a single dose will include a non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate ranging from about 0.5 grams to about 25 grams, or about 0.75 grams to about 20 grams , or about 1 grams to about 15 grams, or about 1.5 grams to about 12 grams.
    [046] [046] In some embodiments, ketogenic compositions may include or be administered together with other supplements, such as vitamin D3, vitamins, minerals, and others known in the art.
    [047] [047] In some embodiments, the compositions may also include one or more medium chain fatty acids, fatty acid esters or mono-, di- or triglycerides of medium chain fatty acids in order to provide an additional source of ketone bodies , as discussed here, to sustain ketosis for a longer period of time, compared to if only the non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate is used alone. In some embodiments, the composition is preferably administered so that the ratio of the non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate to medium chain fatty acid (or ester thereof) varies from about 4: 1 to about 1: 4, or from about 2: 1 to about 1: 2, or from about 1.5: 1 to about 1: 1.5. Short-chain fatty acids, esters and glycerides, although less preferred, can be used in addition to or instead of medium-chain fatty acids, fatty acid esters or glycerides thereof.
    [048] [048] In some modalities, the subject preferably follows a ketogenic diet that restricts the intake of carbohydrates and proteins during the period of administration of the composition. In an exemplary modality, the subject can restrict food intake to a ratio of about 65% fat, about 25% protein and about 10% carbohydrates. The resulting therapeutic ketosis provides rapid and sustained keto-adaptation as a metabolic therapy for a wide range of metabolic disorders and provides nutritional support for therapeutic fasting, weight loss and performance enhancement. As such, the composition is typically administered once a day, twice a day or three times a day to a subject who wishes to promote and / or sustain a state of ketosis.
    [049] [049] In a preferred embodiment, ketogenic compositions can be administered via oral administration in solid and / or powder form, as in a powder mixture (for example, powdered gelatin capsules), compressed tablets or another route of administration known to those skilled in the art.
    [050] [050] In some embodiments, multiple doses of the composition are administered over a period of time. The frequency of administration of the composition can vary depending on any of a variety of factors, such as treatment timing of previous treatments, treatment goals, and the like. The duration of administration of the composition (e.g., the length of time the agent is administered) can vary depending on several factors, including the subject's response, desired effect of treatment, etc.
    [051] [051] The amount of the composition to be administered can vary according to factors such as the individual's degree of susceptibility, the individual's age, sex and weight, the individual's idiosyncratic responses, and the like. The "therapeutically effective amount" is the amount needed to promote a therapeutically effective result in vivo (i.e., therapeutic ketosis). According to the present disclosure, an appropriate single dose size is a dose capable of preventing or alleviating (reducing or eliminating) a symptom in a patient when administered one or more times over an appropriate period of time.
    [052] [052] The amount of composition administered will depend on the potency, absorption, distribution, metabolism, and excretion rates of unused ketone bodies, electrolytes, the method of administration, and the particular disorder being treated, as well as other factors known to that of skill in the technique. The dose should be sufficient to affect a desirable response, such as a therapeutic or prophylactic response against a specific disorder or condition, taking into account the severity of the condition to be relieved. The compounds can be administered once or they can be divided and administered over time intervals. It should be understood that the administration can be adjusted according to the individual need and professional judgment of a person who administers or supervises the administration of the compositions.
    [053] [053] The following is a description of an exemplary non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate compositions and other ketogenic compositions useful for elevating ketone levels in a subject, including inducing and / or modulating a ketogenic state in a subject to which they are administered. It should be appreciated that the beta-hydroxybutyrate compounds described in the examples can be in the form of salts, esters, dimers, trimers, oligomers and polymers, as discussed here. The importance of things from the point of view of the examples is the percentages or enantiomeric ratios of S beta-hydroxybutyrate and R beta-hydroxybutyrate. In some cases, the compositions may be a mixture of salts and esters to provide a desired electrolyte balance and / or ketosis modulation.
    [054] [054] A non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate is prepared by mixing one or more compounds of S beta-hydroxybutyrate with a racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate to provide 52% per enantiomeric equivalents of the S beta-hydroxybutyrate enantiomer and 48% by enantiomeric equivalents of the R beta-hydroxybutyrate enantiomer. Because the non-racemic mixture includes less of the R beta-hydroxybutyrate enantiomer, the onset of ketosis is delayed by a certain dosage compared to the same dosage of the racemic mixture. On the other hand, the inclusion of the S beta-hydroxybutyrate enantiomer provides a longer state of ketosis and / or other benefits as disclosed here.
    [055] [055] The non-racemic mixture is readily administered as a ketogenic composition, as in powder form as a dietary supplement mixed with food or drink, in the form of one or more capsules or tablets, or in liquid form as a mouth spray.
    [056] [056] A non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate is prepared by mixing one or more compounds of S beta-hydroxybutyrate with a racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate to provide 53% per enantiomeric equivalents of the S beta-hydroxybutyrate enantiomer and 47% by enantiomeric equivalents of the R beta-hydroxybutyrate enantiomer. Because the non-racemic mixture includes less of the R beta-hydroxybutyrate enantiomer, the onset of ketosis is delayed by a certain dosage compared to the same dosage of the racemic mixture or the non-racemic mixture of Example 1. On the other hand, the inclusion of S beta-hydroxybutyrate enantiomer provides a longer state of ketosis and / or other benefits as disclosed herein, as compared to a composition enriched with the R beta-hydroxybutyrate enantiomer.
    [057] [057] A non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate is prepared by mixing one or more compounds of S beta-hydroxybutyrate with a racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate to provide 55% per enantiomeric equivalents of the S beta-hydroxybutyrate enantiomer and 45% by enantiomeric equivalents of the R beta-hydroxybutyrate enantiomer. Because the non-racemic mixture includes less of the R beta-hydroxybutyrate enantiomer, the onset of ketosis is delayed by a certain dosage compared to the same dosage of the racemic mixture or the non-racemic mixture of Examples 1 and 2. On the other hand, the inclusion of the S beta-hydroxybutyrate enantiomer provides a longer state of ketosis and / or other benefits as disclosed herein, as compared to a composition enriched with the R beta-hydroxybutyrate enantiomer.
    [058] [058] A non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate is prepared by mixing one or more compounds of S beta-hydroxybutyrate with a racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate to provide 57% per enantiomeric equivalents of the S beta-hydroxybutyrate enantiomer and 43% by enantiomeric equivalents of the R beta-hydroxybutyrate enantiomer. Because the non-racemic mixture includes less of the R beta-hydroxybutyrate enantiomer, the onset of ketosis is delayed by a certain dosage compared to the same dosage of the racemic mixture or the non-racemic mixture of Examples 1 to 3. On the other hand, the inclusion of the S beta-hydroxybutyrate enantiomer provides a longer state of ketosis and / or other benefits as disclosed herein, as compared to a composition enriched with the R beta-hydroxybutyrate enantiomer.
    [059] [059] A non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate is prepared by mixing one or more compounds of S beta-hydroxybutyrate with a racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate to provide 60% per enantiomeric equivalents of the S beta-hydroxybutyrate enantiomer and 40% by enantiomeric equivalents of the R beta-hydroxybutyrate enantiomer. Because the non-racemic mixture includes less of the R beta-hydroxybutyrate enantiomer, the initiation of ketosis is delayed by a certain dosage compared to the same dosage of the racemic mixture or the non-racemic mixture of Examples 1 to 4. On the other hand, the inclusion of the S beta-hydroxybutyrate enantiomer provides a longer state of ketosis and / or other benefits as disclosed herein, as compared to a composition enriched with the R beta-hydroxybutyrate enantiomer.
    [060] [060] A non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate is prepared by mixing one or more compounds of S beta-hydroxybutyrate with a racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate to provide 65% per enantiomeric equivalents of the S beta-hydroxybutyrate enantiomer and 35% by enantiomeric equivalents of the R beta-hydroxybutyrate enantiomer. Because the non-racemic mixture includes less of the R beta-hydroxybutyrate enantiomer, the onset of ketosis is delayed by a certain dosage compared to the same dosage of the racemic mixture or the non-racemic mixture of Examples 1 to 5. On the other hand, the inclusion of the S beta-hydroxybutyrate enantiomer provides a longer state of ketosis and / or other benefits as disclosed herein, as compared to a composition enriched with the R beta-hydroxybutyrate enantiomer.
    [061] [061] A non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate is prepared by mixing one or more compounds of S beta-hydroxybutyrate with a racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate to provide 70% per enantiomeric equivalents of the S beta-hydroxybutyrate enantiomer and 30% by enantiomeric equivalents of the R beta-hydroxybutyrate enantiomer. Because the non-racemic mixture includes less of the R beta-hydroxybutyrate enantiomer, the initiation of ketosis is delayed by a certain dosage compared to the same dosage of the racemic mixture or the non-racemic mixture of Examples 1 to 6. On the other hand, the inclusion of the S beta-hydroxybutyrate enantiomer provides a longer state of ketosis and / or other benefits as disclosed herein, as compared to a composition enriched with the R beta-hydroxybutyrate enantiomer.
    [062] [062] A non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate is prepared by mixing one or more compounds of S beta-hydroxybutyrate with a racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate to provide 75% per enantiomeric equivalents of the S beta-hydroxybutyrate enantiomer and 25% by enantiomeric equivalents of the R beta-hydroxybutyrate enantiomer. Because the non-racemic mixture includes less of the R beta-hydroxybutyrate enantiomer, the initiation of ketosis is delayed by a certain dosage compared to the same dosage of the racemic mixture or the non-racemic mixture of Examples 1 to 7. On the other hand, the inclusion of the S beta-hydroxybutyrate enantiomer provides a longer state of ketosis and / or other benefits as disclosed herein, as compared to a composition enriched with the R beta-hydroxybutyrate enantiomer.
    [063] [063] A non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate is prepared by mixing one or more compounds of S beta-hydroxybutyrate with a racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate to provide 85% per enantiomeric equivalents of the S beta-hydroxybutyrate enantiomer and 15% by enantiomeric equivalents of the R beta-hydroxybutyrate enantiomer. Because the non-racemic mixture includes less of the R beta-hydroxybutyrate enantiomer, the initiation of ketosis is delayed by a certain dosage compared to the same dosage of the racemic mixture or the non-racemic mixture of Examples 1 to 6. inclusion of the S beta-hydroxybutyrate enantiomer provides a longer state of ketosis and / or other benefits as disclosed herein, as compared to a composition enriched with the R beta-hydroxybutyrate enantiomer.
    [064] [064] A non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate is prepared by mixing one or more compounds of S beta-hydroxybutyrate with a racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate to provide 90% , 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% by enantiomeric equivalents of the S beta-hydroxybutyrate enantiomer and 10%, 9%, 8%, 7% , 6%, 5%, 4%, 3%, 2%, or 1% by enantiomeric equivalents of the R beta-hydroxybutyrate enantiomer. Because the non-racemic mixture includes substantially less of the R beta-hydroxybutyrate enantiomer, the onset of ketosis is significantly delayed for a given dosage compared to the same dosage of the racemic mixture or the non-racemic mixture of Examples 1 to 9. On the other hand , the inclusion of the S beta-hydroxybutyrate enantiomer provides a longer state of ketosis and / or other benefits as disclosed here.
    [065] [065] A composition comprising one or more S beta-hydroxybutyrate compounds is mixed with a carrier to form a composition with 100% equivalent of S beta-hydroxybutyrate enantiomer and 0% equivalent of R beta-hydroxybutyrate enantiomer. Because the composition does not contain R beta-hydroxybutyrate enantiomer, the initiation of ketosis is significantly delayed for a given dosage compared to the same dosage of racemic mixture or the non-racemic mixture of Examples 1 to 10. On the other hand, the inclusion of S beta-hydroxybutyrate enantiomer provides a delayed and / or longer state of ketosis and / or other benefits as disclosed herein.
    [066] [066] Any of the previous examples is modified by combining the non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate with a dietetically or pharmaceutically acceptable carrier.
    [067] [067] Any of the previous examples is modified by combining the non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate with one or more medium chain triglycerides and / or one or more medium chain fatty acids and / or one or more mono- or diglyceride medium chain fatty acids.
    [068] [068] Any of the previous examples is modified by combining the non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate with one or more supplements, such as vitamin D3, vitamins, minerals, and others known in the art.
    [069] [069] The present invention can be incorporated in other specific forms without departing from its spirit or essential characteristics. The described modalities should be considered in all aspects only as illustrative and not restrictive. The scope of the invention is therefore indicated by the appended claims and not by the previous description. All changes that fall within the meaning and equivalence range of the claims must be adopted within their scope.
    权利要求:
    Claims (22)
    [1]
    1. A composition for administering ketone bodies and body ketone precursors to a subject, comprising: a dietetically or pharmaceutically acceptable carrier; and S beta-hydroxybutyrate or a non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate, CHARACTERIZED by the fact that the composition comprises 52% to 100% by enantiomeric equivalents of S beta-hydroxybutyrate and 48% to 0% by enantiomeric equivalents of R beta-hydroxybutyrate.
    [2]
    2. Composition, according to claim 1, CHARACTERIZED by the fact that the non-racemic mixture contains from 53% to 98% by enantiomeric equivalents of S beta-hydroxybutyrate and 47% to 2% by enantiomeric equivalents of R beta-hydroxybutyrate.
    [3]
    3. Composition, according to claim 1 or 2, CHARACTERIZED by the fact that the non-racemic mixture contains from 55% to 96% by enantiomeric equivalents of S beta-hydroxybutyrate and 45% to 4% by enantiomeric equivalents of R beta- hydroxybutyrate.
    [4]
    4. Composition according to any one of claims 1 to 3, CHARACTERIZED by the fact that the non-racemic mixture contains 57% to 93% by enantiomeric equivalents of S beta-hydroxybutyrate and 43% to 7% by enantiomeric equivalents of R beta-hydroxybutyrate.
    [5]
    5. Composition according to any one of claims 1 to 4, CHARACTERIZED by the fact that the non-racemic mixture contains 60% to 90% by enantiomeric equivalents of S beta-hydroxybutyrate and 40% to 10% by enantiomeric equivalents of R beta-hydroxybutyrate.
    [6]
    6. Composition according to any one of claims 1 to 5, CHARACTERIZED by the fact that the non-racemic mixture contains 65% to 85%
    by enantiomeric equivalents of S beta-hydroxybutyrate and 35% to 15% by enantiomeric equivalents of R beta-hydroxybutyrate.
    [7]
    Composition according to any one of claims 1 to 6, CHARACTERIZED by the fact that the composition comprises one or more S beta-hydroxybutyrate salts.
    [8]
    8. Composition according to claim 7, CHARACTERIZED by the fact that the one or more salts of S beta-hydroxybutyrate comprise at least one of a sodium salt, potassium salt, magnesium salt, calcium salt, salt of transition metal, or amino acid salt.
    [9]
    9. Composition according to claim 8, CHARACTERIZED by the fact that the amino acid salt includes at least one amino acid or amino acid metabolite selected from arginine, lysine, leucine, iso-leucine, histidine, ornithine, citrulline, glutamine or creatine.
    [10]
    10. Composition according to any one of claims 1 to 9, CHARACTERIZED by the fact that the non-racemic mixture contains at least one S beta-hydroxybutyrate ester.
    [11]
    11. Composition according to claim 10, CHARACTERIZED by the fact that the ester of S beta-hydroxybutyrate is a di-ester of a diol and S beta-hydroxybutyrate.
    [12]
    12. Composition according to claim 10, CHARACTERIZED by the fact that the S-beta-hydroxybutyrate ester comprises at least one of ethanol monoester, 1-propanol monoester, 1,3-propanediol monoester, diester 1,3-propanediol, mono- or di-ester of S-1,3-butanediol, mono- or di-ester of R-1,3-butanediol, mono- or di-ester of SR-1,3-butanediol , or glycerin mono-, di-, or triester.
    [13]
    13. Composition according to any one of claims 1 to 12, CHARACTERIZED by the fact that the non-racemic mixture is a solid, such as a powder or crystalline material.
    [14]
    14. Composition according to any one of claims 1 to 13, CHARACTERIZED by the fact that the carrier comprises a powder, a liquid, a tablet, a capsule, a food product, a food additive, a drink, a beverage additive , or a food supplement.
    [15]
    15. Composition according to any one of claims 1 to 14, CHARACTERIZED by the fact that it still comprises vitamin D3, as in an amount of about 5 µg to about 200 µg, or about 10 µg to about 100 µg , or about 15 µg to about 75 µg, or in an amount of about 200 IU to about 8000 IU, or about 400 IU to about 4000 IU, or about 600 IU to about 3000 IU.
    [16]
    16. Composition according to any one of claims 1 to 15, CHARACTERIZED by the fact that it still comprises at least one medium chain fatty acid, or a mono-, di- or triglyceride of at least one medium chain fatty acid.
    [17]
    17. Composition according to claim 16, CHARACTERIZED by the fact that the at least one medium chain fatty acid has 6 to 12 carbons, or 8 to 10 carbons.
    [18]
    18. Composition according to any one of claims 1 to 17, CHARACTERIZED by the fact that it still comprises at least one of (i) a short chain fatty acid, or a mono-, di- or triglyceride of at least one acid short-chain fatty, having less than 6 carbons or (ii) a long-chain fatty acid, or a mono-, di- or triglyceride of at least one long-chain fatty acid, having more than 12 carbons.
    [19]
    19. Composition to control body level of ketone in a subject, CHARACTERIZED by the fact that it comprises: a non-racemic mixture of S beta-hydroxybutyrate and R beta-hydroxybutyrate, in which the non-racemic mixture contains about 52% to 99% by enantiomeric equivalents of S beta-hydroxybutyrate and 48% to 1% by enantiomeric equivalents of S beta-hydroxybutyrate.
    [20]
    20. Method for controlling body level of ketone in a subject, CHARACTERIZED by the fact that it comprises administering to a subject in need thereof a nutritionally or pharmaceutically effective amount of the composition, according to any one of claims 1 to 19.
    [21]
    21. Method, according to claim 20, CHARACTERIZED by the fact that the increase in the body's level of ketone in the subject results in one or more of appetite suppression, weight loss, fat loss, reduced blood glucose level , improved mental attention, increased physical energy, improved cognitive function, reduced traumatic brain injury, reduced diabetes effect, improved neurological disorder, reduced cancer, reduced inflammation, anti-aging, anti-glycation, reduced epilepsy crisis , improved mood, increased stamina, increased muscle mass, or improved body composition.
    [22]
    22. Method, according to claim 20 or 21, CHARACTERIZED by the fact that S beta-hydroxybutyrate results in at least one of: increased endogenous production of R beta-hydroxybutyrate and acetoacetate; endogenous conversion of S beta-hydroxybutyrate into one or both of R beta-hydroxybutyrate and acetoacetate; endogenous conversion of S beta-hydroxybutyrate into fatty acids and sterols; prolonged ketosis;
    metabolism of S beta-hydroxybutyrate independent of conversion to R beta-hydroxybutyrate and / or acetoacetate;
    increased fetal development;
    increase in years of growth;
    reduced endogenous acetone production during ketosis;
    signal by the S beta-hydroxybutyrate that modulates the metabolism of R beta-
    hydroxybutyrate and glucose;
    antioxidant activity;
    acetyl-CoA production.
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    同族专利:
    公开号 | 公开日
    WO2019125693A1|2019-06-27|
    US20190183820A1|2019-06-20|
    AU2018390719A1|2020-07-02|
    CN111655244A|2020-09-11|
    EP3727360A1|2020-10-28|
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    US10245243B1|2019-04-02|
    SG11202005546UA|2020-07-29|
    US10596128B2|2020-03-24|
    CA3086517A1|2019-06-27|
    JP2021506294A|2021-02-22|
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    法律状态:
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